DEVELOPING A TRANSLATABLE PLATFORM FOR REVERSIBLE PLATELET INHIBITION

点击翻译按钮获取中文摘要

Rationale and Overall Objective: Our overall goal is to develop a rapidly reversible antiplatelet agent that inhibits thrombus formation in highly prothrombotic settings such as those encountered during coronary revascularization procedures. Unregulated accumulation of platelets on atheromatous plaques and other thrombogenic surfaces is an absolute prerequisite for thrombus formation, which in turn represents a proximate cause of myocardial infarction, equipment malfunction, ischemic stroke and cardiovascular death(1-3). Antiplatelet drugs represent a direct outgrowth from a rapidly expanding knowledge base of fundamental platelet biology. None of the available antiplatelet therapies prevent the initiating step for thrombus formation- platelet adhesion. Accordingly, developing novel drugs that are engineered specifically to inhibit biologically relevant targets operative in platelet adhesion represents an important step toward addressing an unmet clinical need. Glycoprotein (GP) Ib-IX-V is a platelet adhesion receptor belonging to a leucine-rich repeat family of proteins. Its major function is to initiate platelet aggregation at high-shear stress blood flow, leading to thrombus formation(4). Following GP Ib-lX-V adhesion to von Willebrand Factor (VWF), platelets become activated, undergo cytoskeletal shape change and secrete platelet agonists that recruit additional platelets to the developing thrombus". Along with GP llb/llla, GP Ib-IX-V is the only platelet receptor that has a non-redundant role in hemostasis and thrombosis, with a hemostatic defect less serious than that of GP llb/llla deficiency(4-7). Thus, inhibitors of GP Ib-IX-V - VWF interaction may have the potential to become effective antithrombotic drugs with a more favorable safety proflle than GP llb/llla inhibitors. The overall effectiveness of antithrombotic therapy for managing patients with thrombotic disorders, particularly those requiring either invasive procedures or surgery has been limited in large part by the attendant bleeding risk which accompanies these therapies. While the responsible mechanisms are poorly defined, concomitant impairment of hemostasis and vascular repair have been proposed as likely contributors. We have previously shown that protein-binding oligonucleotides (aptamers), single-stranded nucleic acids that inhibit platelets, their functional ligands and/or coagulation proteins with high speciflcity can be readily reversed with complementary oligonucleotide antidotes(8-10). Of particular relevance to this proposal, we have developed aptamers against VWF that potentiy inhibit thrombosis in mice and antidote oligonucleotides that can rapidly reverse the antiplatelet activity of the aptamers(11) (Sullenger lab unpublished results). This aptamer-antidote strategy potentially offers broad applications, with the development of antithrombotic drugs which could be actively controlled, allowing full pharmacodynamic effects when clinically indicated, followed by rapid titration or complete reversal.